The long term goal of the proposed research is to develop a safe, efficacious, and practical vaccine against the human immunodeficiency viruses (HIV-1 and HIV-2). Although attenuated viruses (e.g., SIVdeltanef) are the currently accepted "gold standard" in protection experiments in the SIV macaque model of AIDS, concerns about the ultimate safety of such vaccines will probably inhibit their widespread acceptance and use. These concerns have prompter us to consider a vaccine approach that exploits the unusual genetic and biologic features of adeno-associated virus (AAV), a non-pathogenic parvovirus. AAV infection in humans is common, entirely asymptomatic, and not associated with disease. In the research proposed herein, we will characterize a novel approach to genetic immunization that exploits recombinant AAV (rAAV) vectors to deliver SIV and HIV genes. In preliminary work, we have made important breakthroughs in packaging methodology that rAAV a pragmatic DNA delivery system. In addition, we have demonstrated that rAAV carrying the SIV gp160 gene can engender a strong antibody response in vaccinated mice. Thus, we are now poised to move forwards with large-scale immunogenicity and challenge trials in the SIV/SHIV model in macaques. In related work, we propose to use rAAV vectors to perform "reverse immunization". The rationale for this approach is simple. From the work of Burton and others, we known that antibodies which broadly neutralize primary HIV-1 isolate are rare in infected humans, and difficult to elicit by immunization. Thus, it might make sense to deliver pre-selected antibody gene(s) as a form of passive or "reverse" immunization. For this purpose, rAAV will be used to deliver genes representing broadly neutralizing antibodies against HIV-1 (like b12). The hope is that high levels of potent and robust antibodies will be delivered to the circulation and will prevent HIV infection in vaccines.